RESUMEN

Herein, a Cs2CO3-promoted N-alkylation of 3-cyano-2(1H)-pyridones containing alkyl groups with diverse alkyl halides to synthesize N-alkyl-2-pyridones over O-alkylpyridines is reported. The use of alkyl dihalides resulted in complex mixtures of N- and O-alkylated products. The primary factor influencing regioselectivity in these reactions is the electronic effects of substituents on the 2(1H)-pyridone ring, as evidenced by the preferential formation of O-alkylpyridines upon the introduction of aryl groups. Remarkably, we efficiently employed CuAAC and Ti(Oi-Pr)4-catalyzed amidation reactions to functionalize N-alkyl-2-pyridones containing propargyl and ester groups, leading to the synthesis of 1,2,3-triazoles and amides, respectively. Moreover, O-alkylpyridines 10 b and 10 d displayed remarkable selectivity toward the A-498 renal cancer cell line with growth inhibition percentages (%GI) of 54.75 and 67.64, respectively. The binding modes of compounds 10 b and 10 d to the PIM-1 kinase enzyme were determined through molecular docking studies.

Asunto(s)

RESUMEN

The present study highlights a novel and advantageous protocol for accessing carbamates through the well-established three-component coupling reaction involving CO2 , amines, and alkyl halides. By employing an immobilized organic base, operating under mild reaction conditions, an array of alkyl carbamates in yields of up to 95 % could be isolated. This approach offers a broad and versatile product scope, allowing for the facile modification of both the amine and alkyl halide reactants. Notably, the pioneering use of an immobilized organic base, specifically the polymer-supported 1,8-diazabicyclo[5.4.0]undec-7-ene (PS-DBU), in this three-component reaction eliminates the need for classical purification steps, streamlining the process. To ensure practicality and sustainability, extensive studies were conducted to verify the recovery and reusability of the polymer-supported DBU catalyst, which consistently maintained the high chemical yield of the carbamates across multiple cycles. Overall, this innovative protocol represents a significant advancement in carbamate synthesis, combining efficiency, generality, and the potential for DBU recycling.

RESUMEN

This is the first study that describes the antifungal and anti-biofilm potential of O-alkylamidoximes against strains of Cryptococcus neoformans and Cryptococcus gattii. In vitro tests have shown that O-alkylamidoximes are capable of inhibiting fungal growth and biofilm formation of the C. neoformans and C. gattii strains, suggesting, from molecular docking, the potential for interaction with the Hsp90. The associations between O-alkylamidoximes and amphotericin B were beneficial. Therefore, O-alkylamidoximes can be a useful alternative to contribute to the limited arsenal of drugs, since they showed a powerful action against the primary agents of Cryptococcosis.

Asunto(s)

RESUMEN

A rapid, efficient, and original synthesis of novel pyrido[3,2,1-de]phenanthridin-6-ones is reported. First, the key cinnamamide intermediates 8a-f were easily prepared from commercial substituted anilines, cinnamic acid, and 2-bromobenzylbromide in a tandem amidation and N-alkylation protocol. Then, these N-aryl-N-(2-bromobenzyl) cinnamamides 8a-f were subjected to a TFA-mediated intramolecular Friedel-Crafts alkylation followed by a Pd-catalyzed direct C-H arylation to obtain a series of potentially bioactive 4-phenyl-4,5-dihydro-6H,8H-pyrido[3,2,1-de]phenanthridin-6-one derivatives 4a-f in good yields. Finally, the toxicological profile of the prepared final compounds, including their corresponding intermediates, was explored through in silico computational methods, while the acute toxicity toward zebrafish embryos (96 hpf-LC50, 50% lethal concentration) was also determined in the present study.

Asunto(s)

RESUMEN

PEGylated protein purification with the required quality attributes has represented a bioengineering challenge and Affinity Monolith Chromatography (AMC) has never been exploited for this goal. This work reports the generation of a heparin-modified affinity monolith disk by reductive alkylation with raised ligand density for its use as chromatographic support in the separation of lysozyme PEGylation reactions (LPRs) with three different PEG sizes (1, 20 and 40 kDa). For immobilized heparin determination a modified toluidine colorimetric assay adapted to microplate format was proposed. The heparin modified-disk was able to differentiate positional isomers of 20 kDa mono-PEGylated lysozyme at neutral pH using a salt linear gradient. Identity of PEG-conjugates was verified by SDS-PAGE and positional isomers were partially characterized by peptide mapping mass spectrometry. 20 kDa mono-PEGylated lysozyme conjugate purity (99.69 ± 0.05%) was comparable with traditional chromatographic methods while productivity (0.0964 ± 0.0001 mg/mL*min) was increased up to 6.1 times compared to that obtained in heparin packed-bed affinity chromatography procedures. The proposed AMC method represents a reliable, efficient, easy-handling, fast and single-step operation for the analysis or preparative isolation of PEGylated proteins containing a heparin binding domain.

Asunto(s)

RESUMEN

Two mixed-valence octadecavanadates, (NH4)2(Me4N)5[VIV12VV6O42I]·Me4NI·5H2O (V18I) and [{K6(OH2)12VIV11VV7O41(PO4)·4H2O}n] (V18P), were synthesized and characterized by single-crystal X-ray diffraction analysis and FTIR, Raman, 51V NMR, EPR and UV/Vis/NIR spectroscopies. The chemoprotective activity of V18I and V18P towards the alkylating agent diethyl sulfate was assessed in E. coli cultures. The complex V18I was nontoxic in concentrations up to 5.0 mmol L-1, while V18P presented moderate toxicity in the concentration range 0.10 - 10 mmol L-1. Conversely, a ca. 35% enhancement in culture growth as compared to cells treated only with diethyl sulfate was observed upon addition of V18I (0.10 to 2.5 mmol L-1), while the combination of diethyl sulfate with V18P increased the cytotoxicity presented by diethyl sulfate alone. 51V NMR and EPR speciation studies showed that V18I is stable in solution, while V18P suffers partial breakage to give low nuclearity oxidometalates of vanadium(V) and (IV). According to the results, the chemoprotective effect depends strongly on the direct reactivity of the polyoxidovanadates (POV) towards the alkylating agent. The reaction of diethyl sulfate with V18I apparently produces a new, rearranged POV instead of poorly-reactive breakage products, while V18P shows the formation and subsequent consumption of low-nuclearity species. The correlation of this chemistry with that of other mixed-valence polyoxidovanadates, [H6VIV2VV12O38PO4]5- (V14) and [VIV8VV7O36Cl]6- (V15), suggests a relationship between stability in solution and chemoprotective performance.

Asunto(s)

RESUMEN

The continuous prospection for molecules that may be useful in the development of new therapeutic agents is a highly relevant issue, mainly because the launch of new drugs on the market does not accompany the emergence of new resistant microorganisms. In this context, this work describes the synthesis of new O-alkylamidoximes and the evaluation of its antifungal activity. The new O-alkylamidoximes were prepared using easy synthetic protocols and tested against three Candida species using the broth microdilution method. The synthesized compounds were obtained in moderate to good yields in high purity and without any observable decomposition. All tested compounds shown moderate antifungal activity against at least one strain of Candida. Despite the moderate activity of the new compounds, this was the first report involving the antifungal activity of O-alkylamidoximes. In view of the low chemotherapy arsenal and the development of fungal strains resistant to traditional antifungal agents, the present study opens new possibilities for the preparation of a new class of more active antifungal agents.

Asunto(s)

RESUMEN

4-Oxoquinolines are a class of organic substances of great importance in medicinal chemistry, due to their biological and synthetic versatility. N-1-Alkylated-4-oxoquinoline derivatives have been associated with different pharmacological activities such as antibacterial and antiviral. The presence of a carboxamide unit connected to carbon C-3 of the 4-oxoquinoline core has been associated with various biological activities. Experimentally, the N-ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide occurs at the nitrogen of the oxoquinoline group, in a regiosselective way. In this work, we employed DFT methods to investigate the regiosselective ethylation reaction of N-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxamide, evaluating its acid/base behavior and possible reaction paths.

RESUMEN

Organophosphates (OPs) constitute many toxic agrochemicals and warfare and can undergo a wide spectrum of mechanisms, some which are fairly unexplored. In this sense, concise mechanistic elucidation stands out as a strategic tool for achieving efficient detoxification and for monitoring processes. Particularly intriguing is the effect of substituting the oxygen atom of the phosphoryl moiety (P=O) in OPs with a sulfur atom to give the thio-derived OPs (i.e., OTPs, P=S). In general, imidazole (IMZ) reacts very efficiently with OPs by targeting the phosphorus atom, although herein we evidence a thio-driven shift with OTPs: IMZ undergoes unusual nucleophilic attack at the aliphatic carbon atom of methyl parathion. Alkylation of IMZ under mild conditions (aqueous weakly basic medium) is also novel and should be applicable to other novel IMZ-based architectures, and thereby, it can be a great ally for organic synthesis. Overall, a broader understanding of the mechanistic trend involved in such highly toxic agents is provided.

RESUMEN

Molecular targeted compounds are emerging as a strategy to improve classical chemotherapy. Herein, we describe that using low dose of the multikinase inhibitor sorafenib improves cyclophosphamide antitumor activity by inhibiting angiogenesis, metastasis and promoting tumor healing in MDA-MB231 xenografts and the 4T1-12B syngeneic breast cancer metastasis model. Mechanistic studies in MDA-MB231 cells revealed that alkylation upregulates inflammatory genes/proteins such as COX-2, IL8, CXCL2 and MMP1 in a MEK1/2-ERK1/2-dependent manner. These proteins enrich the secretome of cancer cells, stimulating cell invasion and angiogenesis via autocrine and paracrine mechanisms. Sorafenib inhibits MEK1/2-ERK1/2 pathway thereby decreasing inflammatory genes and mitigating cell invasion and angiogenesis at basal and alkylation-induced conditions whereas NRF2 and ER stress pathways involved in alkylation survival are not affected. In non-invasive/non-angiogenic breast cancer cells (SKBR3 and MCF7), alkylation did not elicit inflammatory responses with the only sorafenib effect being ERK1/2-independent ROS-dependent cytotoxicity when using higher drug concentrations. In summary, our data show that alkylating agents may elicit inflammatory responses that seems to contribute to malignant progression in specific breast cancer cells. Identifying and targeting drivers of this phenotype may offer opportunities to optimize combined drug regimens between classical chemotherapeutics and targeted agents.

Asunto(s)

RESUMEN

According to the principles of the methodology of bioisosteric replacements a series of methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates has been obtained as potential analgesics. In addition, a fundamentally new strategy for the synthesis of compounds of this chemical class involving the introduction of N-alkyl substituent at the final stage in 2,1-benzothiazine nucleus already formed has been proposed. Using nuclear magnetic resonance (NMR) spectroscopy, mass spectrometry and X-ray diffraction analysis it has been proven that in the DMSO/K2CO3 system the reaction of methyl 4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylate and alkyl halides leads to formation of N-substituted derivatives with good yields regardless of the structure of the alkylating agent. The peculiarities of NMR (¹Ð and 13С) spectra of the compounds synthesized, their mass spectrometric behavior and the spatial structure are discussed. In N-benzyl derivative the ability to form a monosolvate with methanol has been found. According to the results of the pharmacological testing conducted on the model of the thermal tail-flick it has been determined that replacement of 4-ОН-group in methyl 1-R-4-hydroxy-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates for the methyl group is actually bioisosteric since all methyl 1-R-4-methyl-2,2-dioxo-1H-2λ6,1-benzothiazine-3-carboxylates synthesized demonstrated a statistically significant analgesic effect. The majority of the substances can inhibit the thermal pain response much more effective than piroxicam in the same dose. Under the same conditions as an analgesic the N-methyl-substituted analog exceeds not only piroxicam, but more active meloxicam as well. Therefore, it deserves in-depth biological studies on other experimental models.

RESUMEN

In this work, the synthesis of a series of 2-arylazoimidazole derivatives 6-20 has been achieved through the reaction of imidazole with aryldiazonium salts, followed by ultrasound-assisted alkylation. This approach has important advantages including higher yield, shorter reaction times and milder reaction conditions. The structures of the compounds obtained were determined by MS, IR; and 1H and 13C NMR. The anti-Trypanosoma cruzi activity of the 15 compounds obtained was evaluated. Two compounds with piperidino substituents in the carboxamide moiety proved to be effective inhibitors of epimastigote proliferation, obtaining inhibition values comparable to those achieved with the reference drug Benznidazole. Besides, these compounds displayed low cytotoxicity on mammalian cells. In vivo, both compounds protected mice against a challenge with a lethal Trypanosoma cruzi strain. These results allow us to propose 2-arylazoimidazoles as lead compounds for the design of novel drugs to treat Chagas' disease.

Asunto(s)

RESUMEN

A diversity-oriented approach for the synthesis of various structurally different prenylated alcohols from readily accessible and common precursors was developed. With varying approaches, this article describes some successful examples of a Friedel-Crafts alkylation using methoxyphenols and different prenyl alcohols (geraniol and (E,E)-farnesol). We demonstrated that just by varying the stoichiometry of the Lewis acid used, the course of the reaction can be shifted to produce the alkylated or the cyclized product. Eighteen unique products were obtained with good isolated yields by direct alkylation with or without a consecutive π-cationic cyclization.

Asunto(s)

RESUMEN

Benzene alkylation with propylene was studied in the gas phase using a catalytic membrane reactor and a fixed-bed reactor in the temperature range of 200-300 °C and with a weight hourly space velocity (WHSV) of 51 h-1. ß-zeolite was prepared by hydrothermal synthesis using silica, aluminum metal and TEAOH as precursors. The membrane's XRD patterns showed good crystallinity for the ß-zeolite film, while scanning electron microscopy SEM results indicated that its random polycrystalline film was approximately 1 µm thick. The powders' specific area was determined to be 400 m²×g-1 by N2 adsorption/desorption, and the TPD results indicated an overall acidity of 3.4 mmol NH3×g-1. Relative to the powdered catalyst, the catalytic membrane showed good activity and product selectivity for cumene.

RESUMEN

En este trabajo se reporta el estudio experimental de la alquilación intramolecular de Friedel-Crafts de orto-alilanilinas N-bencilo sustituidas, que explica desde los puntos de vista cinético y termodinâmico la formación de dihidrodibenzo [b,e]azepinas y tetrahidrodibenzo[b, ƒ] azocinas. El seguimiento de los cambios en concentración resultantes del tratamiento en condiciones heterogéneas se llevó a cabo por Cromatografía de Gases-Detector de Ionización en Llama (CG-DILL), mientras que la espectroscopia Ultravioleta-Visible (UV-Vis) y el análisis quimiométrico con el Método Multivariante de Resolución de Curvas-Mínimos Cuadrados Alternados (MMRC-MCA) se usaron para examinar los efectos de las condiciones de reacción en fase homogénea e in situ. Con los resultados obtenidos se puede concluir que la supervisión de parámetros, tales como constantes de velocidad y energías de activación, hizo posible evidenciar los efectos de sustituyen-te, temperatura, velocidad de agitación y concentración, sobre la velocidad y re-gioselectividad de la reacción.

In this work, experimental studies of intramolecular Friedel-Crafts alkylation of N-benzyl sustituted ortho-allylanilines are reported; the results explain the formation of both dihydrodibenz[b,e]azepine and tetrahydrodibenz[b,ƒ]azocine isomers from kinetic and thermodynamic points of view. The concentration changes resulting from treatment under heterogeneous conditions were followed by Gas Chromatography-Flame Ionization Detector (GC-FID), while Ultraviolet-Visible (UV-Vis) spectroscopy with Multivariate Curve Resolution-Alternating Least Squares (MCR-ALS) chemometric analysis were used for analysis of the effects of reaction conditions in homogeneous phase and in-situ. With the obtained results could be conclude that the supervision of parameters such as rate constants and activation energies proved the effects of substituent, temperature, agitation speed and concentration on reaction velocity and regioselectivity.

No trabalho reporta-se o estudo experimental da alquilação intramolecular de Friedel-Crafts de orto-alil-anilines N-bencil substituídas o quais explicam desde a cinética e a termodinâmica, a produção de dihidrodibenzo[b,e]azepinas e tetrahidrodibenzo[b,ƒ]azocinas. O procedimento experimental nas condições erogén foi estabelecida mediante GC-FID e a espectroscopia UV-Vis com análise quimiométrico MCR-ALS foi usada para estabelecer as condições da reação na fase homogênea e in situ. Baseados nos resultados obtidos pode-se concluir como variação dos parâmetros constate de velocidade e energia de ativação fize possível evidenciar os efeitos do substituinte, temperatura, velocidade de agitação e concentração, sobra a velocidade e seletividade da reação.